Despite the numerous biomarkers reported, few are useful for predicting metastasis. In our recent studies, we have uncovered a novel splice isoform of the prohormone processing enzyme, carboxypeptidase E (CPE-deltaN) that is elevated in metastatic hepatocellular, colon, breast, prostate, head and neck carcinoma cells. CPE-deltaN lacks the N-terminus that is normally present in secretory granule wild-type CPE, and is localized to the nucleus of metastatic cancer cells. Overexpression of CPE-deltaN in hepatocellular carcinoma (HCC) cells promoted their proliferation and migration by up-regulating expression of a metastasis gene via epigenetic mechanisms. SiRNA knockdown of CPE-deltaN expression in highly metastatic HCC cells inhibited their growth and metastasis in nude mice. In retrospective clinical studies, CPE-deltaN RNA quantification in primary HCC and colon tumors from patients established a level, above which predicted metastasis with high prognostic significance (p<0.0001). Furthermore, in a prospective clinical study on patients with paragangliomas, we were able to successfully predict from the mRNA copy numbers of CPE-deltaN of the resected tumors of several patients who were initially diagnosed as having benign tumors, that they would develop metastasis in the future. Indeed subsequent follow-up of these patients revealed development of metastasis over several years. Thus, CPE-deltaN is a new mediator of tumor metastasis and a powerful prognostic marker.